Caenorhabditis elegans LET-767 is able to metabolize androgens and estrogens and likely shares common ancestor with human types 3 and 12 17β-hydroxysteroid dehydrogenases

Abstract

Mutations that inactivate LET-767 are shown to affect growth, reproduction, and development in Caenorhabditis elegans. Sequence analysis indicates that LET-767 shares the highest homology with human types 3 and 12 17b-hydroxysteroid dehydrogenases (17b-HSD3 and 12). Using LET-767 transiently transfected into human embryonic kidney-293 cells, we have found that the enzyme catalyzes the transformation of both 4-androstenedione into testosterone and estrone into estradiol, similar to that of mouse 17b-HSD12 but different from human and primate enzymes that catalyze the transformation of estrone into estradiol. Previously, we have shown that amino acid F234 in human 17b-HSD12 is responsible for the selectivity of the enzyme toward estrogens. To assess whether this amino acid position 234 in LET-767 could play a role in androgen-estrogen selectivity, we have changed the methionine M234 in LET-767 into F. The results show that the M234F change causes the loss of the ability to transform androstenedione into testosterone, while conserving the ability to transform estrone into estradiol, thus confirming the role of amino acid position 234 in substrate selectivity. To further analyze the structure-function relationship of this enzyme, we have changed the three amino acids corresponding to lethal mutations in let-767 gene. The data show that these mutations strongly affect the ability of LET-767 to convert estrone into estradiol and abolish its ability to transform androstenedione into testosterone. The high conservation of the active site and amino acids responsible for enzymatic activity and substrate selectivity strongly suggests that LET-767 shares a common ancestor with human 17b-HSD3 and 12.

LET-767 Is Required for the Production of Branched Chain and Long Chain Fatty Acids in Caenorhabditis elegans

“…We could not exclude that, in addition to 3-ketoacyl-CoA reductase activity, LET-767 might also be involved in another activity (e.g. production of steroids proposed earlier (18,19)), which, however, does not lead to the developmental arrest caused by depletion of LET-767, because addition of fatty acids is sufficient to overcome it.…”

“…5D). It was previously suggested that LET-767 might produce steroid hormones, such as testosterone (19). To check whether steroids might also be important for let-767 (RNAi) developmental arrest, we supplemented the worms with testosterone alone or in combination with fatty acids.…”

“…Based on mutant morphological phenotypes, it was proposed that let-767 encodes a sterol-modifying enzyme that might be involved in the production of a molting hormone (18). Recently, it has been shown that LET-767 can catalyze the transformation of 4-an-drostendione into testosterone and estrone into estradiol when the enzyme was expressed in HEK-293 cells and the cells were challenged with high concentrations of the substrates (19). However, in worm cells, in its native biochemical environment, LET-767 might have a different activity.…”

Origin and diversification of steroids: Co-evolution of enzymes and nuclear receptors

“…Indeed, high affinity binding for E2 is found in vertebrate ERs, rat and mouse alpha-fetoprotein and sex steroid binding globulin [13], as well as in enzymes in yeast [51], which do not have steroid receptors. Another example of convergence is the presence of over ten 17 -hydroxysteroid dehydrogenases that metabolize estrogens and androgens [13][14]52]. …”

WW Domain-Containing Oxidoreductase is a Potential Receptor for Sex Steroid Hormones

“…17 -HSD12 catalyzes the transformation of both androgens and estrogens Liu et al, 2007). Caenorhabditis elegans LET-767 is known to metabolize androgens and estrogens, and the gene appears to share a common ancestor with human types 17 -HSD3 and HSD12 (Desnoyers et al, 2007). High levels of expression of 17 -HSD1 have been shown to be associated with poor prognosis in breast cancer and late relapse among patients with ER-positive breast tumors (Sasaki et al, 2010;Jansson et al, 2009).…”